Novel CAR T Therapy Shows Responses, Expansion in R/R Myeloma

"These CAR T cells exhibit robust expansion in vivo followed by long-term persistence in 50% of the patients, and long-term persistence of CAR positive T cells was associated with suppression of soluble BCMA," according to Shuntaro Ikegawa, MD, PhD.

CAR T therapy with durcabtagene autoleucel (PHE885) exhibited responses, rapid expansion in vivo, and persistence in the long term among patients with relapsed/refractory multiple myeloma, according to data presented at the 2023 International Myeloma Society Annual Meeting.¹

Using the T-Charge platform, the B-cell maturation antigen (BCMA)-targeted CAR T cells were produced, and correlative analysis was performed in 31 patients with heavily pretreated multiple myeloma at Dana-Farber Cancer Institute in a phase 1 study (NCT04318327).

“This CAR T cell is manufactured in less than 2 days using the T-Charge platform, which is much shorter than the conventional CAR T cell manufacturing process,” explained Shuntaro Ikegawa, MD, PhD, a research fellow at Dana-Farber Cancer Institute, during his oral abstract presentation.

Whereas traditional CAR T cells undergo expansion ex vivo for 7 to 10 days before infusion, durcabtagene autoleucel is infused earlier with a lower dose and expansion takes place in patients, which Ikegawa said may promote or preserve T-cell stemness and their function.

Investigators in the phase 1 dose expansion study previously reported positive efficacy and safety results at the 2023 American Society for Clinical Oncology Annual Meeting from 46 patients.² The patients were able to proceed from apheresis to lymphodepletion in a median of 16 days, and only 28% required bridging therapy due primarily to the quick production time.

At a data cutoff of March 28, 2023, 31 patients treated at Dana-Farber Institute with a median age of 65 years had received doses ranging from 2.5 × 10⁶ to 20 × 10⁶ T cells.¹ Ninety-four percent of patients had triple-class refractory multiple myeloma. Twenty-six patients (84%) had received prior hematopoietic stem cell transplant.

All patients responded except for 1 patient who received the lowest dose level, for an overall response rate of 97% including a stringent complete response rate of 38.7%, very good partial response rate of 38.7%, and partial response rate of 19.4%.

Investigators analyzed CAR T-cell kinetics of fresh blood from all patients by flow cytometry, and also analyzed the apheresis sample, CAR T-cell final product, and post-infusion peripheral blood mononuclear cell by mass cytometry and T-cell sequence from the first 15 patients, including 4 who received 2.5 × 10⁶ cells, 10 who received 5 × 10⁶ cells, and 1 who received 14.3 × 10⁶ cells.

“All patients showed robust CAR T-cell expansion which peaked on day 14, and at the time of peak expansion, most patients’ CAR T cells were presenting more than 50% of the circulating T cells,” said Ikegawa.

Some patients continued to show a high number of circulating T cells in the peripheral blood at 1 year or later. CAR T cell expansion was associated with inflammatory cytokine elevation, which Ikegawa said was consistent with other reports on CAR T expansion.

Investigators also measured soluble BCMA level from baseline and in the post-infusion period. In 22 patients who were followed for more than 9 months, 11 had longer CAR T cell persistence had lower levels of soluble BCMA, suggesting that they maintained their functional activity against BCMA over this period.

Apheresis samples were compared with the final CAR T cell product; CD3 stemlike memory T cells (Tscm) increased and CD3 naïve T cells decreased, suggesting that the T-Charge process caused this shift during manufacturing.

Comparing the T cell diversity between Tscm cells and memory cells in the final product showed it was more heterogeneous in the Tscm cells in the CAR T final product for both CD4 and CD8. After infusion of the CAR T cells, CAR positive T cells had higher diversity than CAR negative T cells in CD4 T cells and CD8 T cells.

The T-cell receptor repertoire of post-infusion CAR positive T-cells also appeared to be more similar to Tscm repertoire than the memory T cells in the produced CAR T cells in both CD4 and CD8, suggesting that they were derived from the Tscm cells from the CAR T cell product.

“These CAR T cells exhibit robust expansion in vivo followed by long-term persistence in 50% of the patients, and long-term persistence of CAR positive T cells was associated with suppression of soluble BCMA,” concluded Ikegawa.

References

1. Ikegawa S, Prabhala RH, Sperling AS, et al. Robust in vivo expansion and long-term persistence of anti-BCMA CAR T cells, PHE885, manufactured in < 2 days on the T-Charge platform. Presented at: International Myeloma Society 20th Annual Meeting and Exposition; September 27-30, 2023; Athens, Greece. OA-06.
2. Sperling AS, Derman BA, Nikiforow S, et al. Updated phase I study results of PHE885, a T-Charge manufactured BCMA-directed CAR-T cell therapy, for patients (pts) with r/r multiple myeloma (RRMM). J Clin Oncol. 2023;41(16_suppl):8004. doi:10.1200/JCO.2023.41.16_suppl.8004